We have previously demonstrated that select viral antigens, including human immunodeficiency virus (HIV) itself, can stimulate human macrophages (MO) to secrete monokines capable of upregulating HIV expression in chronically infected human cells. Subsequent investigations to determine which HIV proteins were capable of stimulating monokine production revealed that the natural gpl2O envelope protein could mediate this response, whereas the natural capsid protein could not. Our recent analyses utilizing recombinant HIV proteins demonstrate that proteins expressed in baculovirus (including gpl6O and gpl2O envelope proteins and p66 reverse transcriptase; MicroGeneSys, Inc.) are unable to stimulate HIV-enhancing monokine activity. Similarly, a recombinant gpl2O fusion protein (Genentech, Inc.) expressed in Chinese hamster ovary cells is unable to induce monokine production. However, a full-length recombinant gpl2O expressed in CHO cells (Cell Tech, Inc.) is capable of stimulating monokine production. Monokine secretion caused by natural gpl2O or this latter recombinant can not be attributed to contaminating endotoxin. Furthermore, the monokine secretion caused by natural gpl2O can be blocked using either soluble CD4 or the recombinant gpl2O fusion protein. Thus, the HIV envelope glycoprotein may indirectly augment HIV expression by stimulating monokine secretion. However, subtle differences may exist in gpl2O preparations which would influence this effect on human MO.